The proposed research is for the fourth competitive renewal of a long-term project to define the molecular basis of the muscular dystrophies. Previous awards have been used to define novel causes of muscular dystrophy, conduct genotype/phenotype correlations, probe molecular mechanisms of the different types, and to develop sensitive and specific molecular tests. During the previous award period, the applicant turned to genome-wide expression profiling of patient muscle biopsy RNA to interrogate both molecular pathophysiology of Duchenne muscular dystrophy, as well as continuing work on new genetic causes of muscular dystrophy. The new preliminary data on a 128 muscle biopsy whole-genome (U133A/B) profiling study demonstrates proof of principle that novel biochemical pathways can be defined using large scale data modeling and statistical analyses. Specifically, the investigators define a temporal pathway of Lamin A/C-Rb-MyoD in muscle regeneration that is specifically perturbed in Emery-Dreifuss muscular dystrophy. The proposed aims are to extend this data analysis into the poorly defined and heterogeneous Limb-girdle muscular dystrophy group of disorders. This new application is very heavily oriented towards large-scale data generation, data modeling and statistical analyses. The specific aims are: 1. to develop mRNA fingerprints diagnostic of the most common known causes of limb-girdle muscular dystrophy (LGMD); 2. to define biochemical pathways for Limb-girdle muscular dystrophy from the profiling data, as has been done for Emery-Dreifuss dystrophy; 3. extend data modeling into the definition of novel diagnostic categories of LGMD. The proposed research will be conducted by a collaborative team of molecular geneticists (Drs. Hoffman, Bakay, Zhao), and data modeling and statistical computer scientists and electrical engineers (Drs. Wang, Xuan, Miller). Importantly, all data will be released to the public via a highly evolved web database portal developed by the PI's lab (PEPR), including web-based dynamic data analysis tools.